Alzheimer's disease is a major public health problem for the United States. Up to 4 million older Americans currently suffer with Alzheimer's disease, and up to 12 million are expected to by the year 2020. Rational design of effective therapeutics will require a detailed understanding of the pathophysiology of Alzheimer's disease. The long-term objective of this project is to understand how different isoforms of apolipoprotein E specifically modify the distribution and amount of neurotoxic lipid peroxidation products in the brain, thereby contributing to the stratification of risk for Alzheimer's disease with apolipoprotein E genotype. The specific aims of this application are: 1) to determine the mechanisms of apoE isoform-specific distribution of human native central nervous system lipoproteins by quantifying cell surface receptor binding, internalization, and degradation of human central nervous system lipoproteins in cultured neurons and astrocytes; 2) to determine the pathogenicity of apolipoprotein E isoform-directed delivery of oxidized central nervous system lipoproteins by purifying oxidized central nervous system lipoproteins from Alzheimer's disease patients or oxidizing ex vivo central nervous system lipoproteins from control subjects and quantifying their neurodegenerative and cytoskeletal damaging effects in neurons and astrocytes; and 3) to quantify regional brain lipid peroxidation in vivo and examine its relationship to differences in the apolipoprotein E gene by quantifying brain regional F2-isoprostanes and F4-neuroprostanes in Alzheimer's disease patients with different apolipoprotein E genotypes and in homozygous apolipoprotein E deficient mice. This new information will aid in laying the foundation for designing rational therapeutic approaches to ameliorate brain oxidative damage in Alzheimer's disease.